Recent advances in small animal imaging and the development of more accurate mouse models of human cancer provide exciting opportunities to improve radiation therapy for patients with lung cancer. The goal of this project is to elucidate molecular mechanisms of lung tumor biology following radiation therapy. Lung adenocarcinomas in mice will be imaged with X-ray computed tomography (CT) and magnetic resonance imaging (MRI) to dissect the cellular and genetic requirements for tumor response to radiation therapy. Cre-lox technology will be used to generate lung cancers with specific gene mutations. In addition, lung tumors will be produced with cell death pathways that are disrupted in tumor cells or in tumor stroma. The response of the tumors to radiation therapy will be compared by CT. These studies will clarify the role of the tumor suppressor gene p53 in the response of lung cancers to radiation therapy, determine whether apoptosis of tumor cells is required for radiation therapy to eradicate lung cancers, and identify the cellular target for radiation therapy. The vascular volume fraction of tumors will be measured with MRI and will be correlated to tumor response after irradiation. In addition, luciferase reporters that are activated during apoptosis will be optimized in cells grown in tissue culture. These reporters will be used to generate transgenic mice to develop a mouse model for in vivo bioluminescence imaging (BLI) of apoptosis. Imaging lung cancer in mice with CT, MRI, and BLI will reveal key mechanisms of how lung cancer responds to radiation therapy. The picture created from these imaging studies will ultimately form the foundation for improved treatment of patients with lung cancer.